Role of Proximal Tubule DPP4 in Inflammation and Kidney Disease Progression

Abstract

Obesity and overweight leads to an entity called obesity related kidney disease (ORKD), which is a major risk factor for chronic kidney disease (CKD) progression to End Stage Renal Disease and/or dialysis. ORKD is characterized by proximal tubule brush border vacuolization and injury, basement membrane thickening, glomerular accumulation of fat globules and glomerulomegaly. We have developed a mouse model of Western diet (high fat and high sucrose)‐induced obesity that manifests all the features of ORKD. In addition, our lab observed that obese mice fed a Western diet, manifest early hyperfiltration (3 months into feeding). It is later followed by reduction in glomerular filtration rate (GFR, beginning at 18 months of age), and this pattern mimics human diabetic kidney disease progression. Our lab also observed that in ORKD, there is increased Dipeptidyl Peptidase 4 (DPP4) activity in the kidney, especially the proximal tubules and proximal tubule specific deletion of DPP4 improves the GFR. Lastly, our lab demonstrated that there is a major role for inflammation in the obese kidney and DPP4 inhibitors mitigate the inflammation. However, it is not known if and how proximal tubule DPP4 contributes to inflammation and pathophysiological changes in ORKD. Therefore, we hypothesized that proximal tubule DPP4 mediates inflammation and contributes to the pathophysiological changes in ORKD, thereby identifying DPP4 as a target to prevent CKD progression.MethodsProximal tubule specific DPP4fl/fl;SGLT2Cre+ (PT DPP4KO) and DPP4fl/fl;SGLT2Cre‐ (PT DPP4WT) mice were fed a WD and control chow (CD) for 6 mths, 15 mths and till sacrifice (18 to 27 mths). Inflammation was assessed both by flow cytometry assessment of kidney immune cells and expression of pro and anti‐inflammatory genes and proteins).ResultsThere were more pro‐inflammatory as well as DPP4 expressing macrophages in the WD‐fed WT group compared to the KO group (p<0.05). There was also activation of the T‐cells in particular the CD8s which was suppressed in the KO group (p<0.05). Deep sequencing of kidney mRNA revealed activation of pro‐inflammatory cytokines including Th1, Th17, M1 macrophage‐based cytokines and TLR4 and ICAM‐1. The KO group showed improvement in both TLR4 and ICAM‐1 (p<0.05). At the protein level, there was an increase in pro‐fibrotic (Desmin) and pro‐inflammatory (ERK) proteins in the WD‐fed WT groups and phosphorylation of ERK was suppressed in the KO group (p<0.05). When inflammation was assessed across the months it seemed that the earliest changes were in the growth pathways and beta‐oxidation of lipids, followed by the more inflammatory genes later in the course of the disease.ConclusionWD feeding led to hyperfiltration followed by a decline in GFR that was partly mitigated by PT deletion of DPP4 and this was associated with improved kidney histology and less fibrosis. WD feeding in WT mice was associated with increase in expression of several pro inflammatory genes and TLR4 and ICAM 1 were normalized in KO mice. DPP4 protein expression in kidney was associated with increased phosphorylation of ERK and this was suppressed in KO mice. Overall, these data suggest that suppression of early activation of DPP4 in ORKD may slow down the progression of CKD.